The goal of this project is to elucidate changes in neural mechanisms induced by exposure to environmental tobacco smoke (ETS) during critical developmental windows in early life and which lead to increased susceptibility and occurrence of adult asthma. Exposure to ETS in utero or during early postnatal development increases the incidence of respiratory illnesses later in life. The mechanisms of enhanced susceptibility in early life and the basis for defining critical windows of vulnerability are not well understood. The nervous system is highly susceptible to environmental influences during development, including the nerves supplying the airways. Airway innervation develops rapidly during fetal and early postnatal life in parallel with the developing lung. Given the dynamic and vulnerable nature of developmental processes, this period of morphogenesis is likely to be exquisitely sensitive to environmental insults. Substance P (SP), a neurotransmitter synthesized and released from airway sensory nerve, plays an important role in antigen or irritant-induced asthma. SP can trigger symptoms of bronchial asthma including airway smooth muscle constriction and acute inflammation. Interestingly, recent studies in our laboratory showed that nerve growth factor (NGF) generated by irritant exposure mediated the changes in SP phenotype and neuronal responses. Thus, we hypothesize that the levels of SP in the airway neurons and airway wall are permanently altered by exposure to ETS in early life. Further, we hypothesize that these changes are mediated through NGF and are manifest as increased neural responsiveness that in turn promotes airway hyperreactivity and increased susceptibility to asthma in later life. The specific aims are to 1). identify critical windows of susceptibility to ETS by measuring SP in neurons innervating the airway and dynamic changes in lung function, 2). determine the effects of NGF limitation during critical developmental periods in the ETS-induced modulation of SP regulating airway hyperreactivity. If our hypotheses are correct, the study will show that growth factor expression is responsible for altered neurotransmitter regulation in adults during critical exposure windows. The findings will provide new understanding about the mechanisms of ETS susceptibility during early life. [unreadable] [unreadable] [unreadable]